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m6A alters ribosome dynamics to initiate mRNA degradation

Shino Murakami1, Anthony O Olarerin-George2, Jianheng Fox Liu1

  • 1Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.

Cell
|May 6, 2025
PubMed

Insights

N6-methyladenosine (m6A) in mRNA triggers ribosome stalling and collisions, initiating mRNA degradation. This process is crucial for cell growth and stress responses, with ribosomes acting as the initial m6A sensor.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) modification is vital for cellular processes like growth and differentiation.
  • The precise mechanisms by which m6A influences mRNA fate, particularly degradation, are not fully understood.

Purpose of the Study:

  • To investigate the impact of m6A on ribosome dynamics.
  • To elucidate how m6A-induced alterations in ribosome behavior mediate mRNA degradation.
  • To identify the ribosome's role as an initial sensor in m6A-mediated mRNA decay.

Main Methods:

  • Analysis of ribosome dynamics in the presence of m6A.
  • Observation of ribosome stalling and collision events.
  • Correlation of ribosome collision persistence with mRNA degradation rates.
  • Investigation of YTHDF m6A reader protein recruitment.
  • Study of translation suppression effects on m6A-mRNA stability.

Main Results:

  • m6A significantly alters ribosome dynamics, inducing potent ribosome stalling.
  • m6A-induced stalls lead to unique ribosome collisions that correlate with mRNA degradation.
  • Increased persistence of collided ribosomes enhances m6A-mediated mRNA degradation.
  • YTHDF reader proteins are recruited following ribosome stalling and collision.
  • Reduced ribosome stalling and collisions stabilize m6A-mRNAs, aiding stress responses.

Conclusions:

  • The ribosome acts as the primary sensor for m6A modification, initiating mRNA degradation.
  • Ribosome stalling and collision are key mechanistic intermediates in m6A-mediated mRNA decay.
  • Modulating ribosome dynamics offers a potential strategy to control m6A-mRNA levels during cellular stress.
Keywords:
N(6)-methyladenosineTimeLapse-seqadaptive responseamino acid depletionm(6)AmRNA decaymRNA degradationmRNA stabilityribosome collisionribosome stall

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